WO2021054997A1 - Compositions et procédés de génération d'un plasma pauvre en agent cryogénique modifié - Google Patents

Compositions et procédés de génération d'un plasma pauvre en agent cryogénique modifié Download PDF

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Publication number
WO2021054997A1
WO2021054997A1 PCT/US2020/012860 US2020012860W WO2021054997A1 WO 2021054997 A1 WO2021054997 A1 WO 2021054997A1 US 2020012860 W US2020012860 W US 2020012860W WO 2021054997 A1 WO2021054997 A1 WO 2021054997A1
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Prior art keywords
modified
precipitant
plasma
cryoprecipitate
cryo
Prior art date
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PCT/US2020/012860
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English (en)
Inventor
Eugene ZURLO
Dennis Curtin
Peter Radtke
Kurt L. Brillhart
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Plasma Technologies, Llc
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Publication of WO2021054997A1 publication Critical patent/WO2021054997A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/14—Extraction; Separation; Purification
    • C07K1/16—Extraction; Separation; Purification by chromatography
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/76—Albumins
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N1/00—Preservation of bodies of humans or animals, or parts thereof
    • A01N1/02—Preservation of living parts
    • A01N1/0205—Chemical aspects
    • A01N1/021—Preservation or perfusion media, liquids, solids or gases used in the preservation of cells, tissue, organs or bodily fluids
    • A—HUMAN NECESSITIES
    • A01—AGRICULTURE; FORESTRY; ANIMAL HUSBANDRY; HUNTING; TRAPPING; FISHING
    • A01N—PRESERVATION OF BODIES OF HUMANS OR ANIMALS OR PLANTS OR PARTS THEREOF; BIOCIDES, e.g. AS DISINFECTANTS, AS PESTICIDES OR AS HERBICIDES; PEST REPELLANTS OR ATTRACTANTS; PLANT GROWTH REGULATORS
    • A01N1/00—Preservation of bodies of humans or animals, or parts thereof
    • A01N1/02—Preservation of living parts
    • A01N1/0278—Physical preservation processes
    • A01N1/0284—Temperature processes, i.e. using a designated change in temperature over time
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/745—Blood coagulation or fibrinolysis factors
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/745—Blood coagulation or fibrinolysis factors
    • C07K14/75—Fibrinogen
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/78—Connective tissue peptides, e.g. collagen, elastin, laminin, fibronectin, vitronectin or cold insoluble globulin [CIG]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/81—Protease inhibitors
    • C07K14/8107—Endopeptidase (E.C. 3.4.21-99) inhibitors
    • C07K14/811—Serine protease (E.C. 3.4.21) inhibitors
    • C07K14/8121—Serpins
    • C07K14/8125—Alpha-1-antitrypsin
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/06—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies from serum
    • C07K16/065—Purification, fragmentation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/14—Extraction; Separation; Purification
    • C07K1/30—Extraction; Separation; Purification by precipitation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K1/00—General methods for the preparation of peptides, i.e. processes for the organic chemical preparation of peptides or proteins of any length
    • C07K1/14—Extraction; Separation; Purification
    • C07K1/36—Extraction; Separation; Purification by a combination of two or more processes of different types

Definitions

  • the field of the invention is blood products, in particular serum or plasma
  • the non-cellular portion of human blood has long been used as a source of human proteins for therapeutic use (such as immunoglobulins, albumin, clotting factors, alpha 1 antitrypsin, etc.).
  • proteins for therapeutic use (such as immunoglobulins, albumin, clotting factors, alpha 1 antitrypsin, etc.).
  • blood plasma obtained from commercial donation centers.
  • proteins need to be isolated at high purity, while minimizing denaturation. In order to be successful commercial endeavors need to recover these proteins in high yield and purity by scalable processes.
  • Methods and compositions of the inventive concept provide a modified cryoprecipitation procedure that generates a modified cryo-poor plasma preparation suitable for direct application to chromatography without intervening precipitation steps.
  • One embodiment of the inventive concept is a method for making a modified cryo-poor plasma, by thawing frozen plasma at a temperature of from about 1 °C to about 6 °C in the presence of a precipitant to generate a modified cryoprecipitate and a modified cryo-poor plasma.
  • the precipitant is supplied in a concentration that does not result in formation of a visible precipitate when the concentration is provided to non-frozen plasma.
  • the resulting modified cryoprecipitate can then be separated from the modified cryo-poor plasma.
  • Suitable precipitants include, but are not limited to, organic acids, salts of organic acids (such as sodium citrate), inorganic salts, and hydrophilic polymers.
  • the resulting modified cryoprecipitate can have an increased content of cold-insoluble proteins relative to a conventional cryoprecipitate generated by thawing the frozen plasma at a temperature of from about 1 °C to about 6 °C in the absence of the precipitant.
  • the modified cryo-poor plasma has a decreased content of cold-insoluble proteins or denatured proteins relative to a conventional cryo-poor plasma generated by thawing the frozen plasma at a temperature of from about 1 °C to about 6 °C in the absence of the precipitant.
  • Another embodiment of the inventive concept is a method for isolating a protein from plasma, by thawing frozen plasma at a temperature of from about 1 °C to about 6 °C in the presence of a precipitant to generate a modified cryoprecipitate and a modified cryo-poor plasma, separating the modified cryoprecipitate from the modified cryo-poor plasma, applying the modified cryo-poor plasma to a chromatography media without an intervening precipitation, filter separation by molecular weight/size (e.g. ultrafiltration, diafiltration), and/or significant dilution step to produce an unbound and bound fractions, and recovering the protein of interest (e.g.
  • the precipitant can be supplied in a concentration that does not result in formation of a visible precipitate in non-frozen plasma.
  • Suitable precipitants include organic acids, salts of organic acids (such as sodium citrate), inorganic salts, and hydrophilic polymers.
  • the modified cryoprecipitate so produced can have an increased content of cold-insoluble proteins relative to a conventional cryoprecipitate generated by thawing the frozen plasma at a temperature of from about 1 °C to about 6 °C in the absence of the precipitant.
  • the modified cryo-poor plasma can have a decreased content of cold-insoluble proteins or denatured proteins relative to a conventional cryo-poor plasma generated by thawing the frozen plasma at a temperature of from about 1 °C to about 6 °C in the absence of the precipitant.
  • Suitable chromatography media include but are not limited to size exclusion media, ion exchange media, hydrophobic interaction media, affinity media, and mixed-mode media.
  • the modified cryoprecipitate is further processed by solublizing the cryoprecipitate and isolating a second protein (e.g. fibrinogen, fibronectin, a clotting factor) from the cryoprecipitate.
  • a second protein e.g. fibrinogen, fibronectin, a clotting factor
  • Another embodiment of the inventive concept is a process intermediate that includes a precipitant, a modified cryoprecipitate (which includes an increased content of cold-insoluble proteins relative to a conventional cryoprecipitate generated by thawing the frozen plasma at a temperature of from about 1 °C to about 6 °C in the absence of the precipitant), and a modified cryo-poor plasma (which includes a decreased content of cold-insoluble proteins or denatured proteins relative to a conventional cryo-poor plasma generated by thawing the frozen plasma at a temperature of from about 1 °C to about 6 °C in the absence of the precipitant).
  • Suitable precipitants include, but are not limited to, organic acids, salts of organic acids (such as sodium citrate), inorganic salts, and hydrophilic polymers.
  • Typical cold-insoluble proteins include fibrinogen, fibronectin, and clotting factors.
  • FIG. 1 schematically depicts an embodiment of a method of the inventive concept.
  • the numbers expressing quantities of ingredients, properties such as concentration, reaction conditions, and so forth, used to describe and claim certain embodiments of the invention are to be understood as being modified in some instances by the term “about.” Accordingly, in some embodiments, the numerical parameters set forth in the written description and attached claims are approximations that can vary depending upon the desired properties sought to be obtained by a particular embodiment. In some embodiments, the numerical parameters should be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of some embodiments of the invention are approximations, the numerical values set forth in the specific examples are reported as precisely as practicable. The numerical values presented in some embodiments of the invention may contain certain errors necessarily resulting from the standard deviation found in their respective testing measurements.
  • the source material for the vast majority of blood products is frozen plasma obtained from commercial collection centers. Slowly thawing this material at low temperature (typically from 1 to 6 °C) generates an intermediate blood product that contains precipitated proteins (i.e. cryoprecipitate or “cryo”) and a protein-rich supernatant (cryo-poor plasma). Cryoprecipitate includes some of the fibrinogen content of the source plasma, as well as clotting factors and fibrin. Cryo-poor plasma is rich in cold-soluble proteins and is frequently used as a source of pharmaceutical proteins.
  • Cryo-poor plasma has a protein content and/or denatured protein content that renders it unsuitable for direct application to conventional chromatographic separations without an intervening dilution or processing step.
  • a precipitant i.e. a concentration that does not result in observable precipitation when applied to serum and/or plasma
  • the resulting modified cryo-poor plasma has been found to have a protein content that permits direct application to chromatography media (e.g.
  • the chromatography media is an affinity media. This advantageously both simplifies and reduces the time and materials required for plasma processing time. In addition, reduction in the number of processing steps can reduce the degree to which sensitive protein species are denatured, resulting in improved stability and specific activity.
  • inventive subject matter provides many example embodiments of the inventive subject matter. Although each embodiment represents a single combination of inventive elements, the inventive subject matter is considered to include all possible combinations of the disclosed elements. Thus, if one embodiment comprises elements A, B, and C, and a second embodiment comprises elements B and D, then the inventive subject matter is also considered to include other remaining combinations of A, B, C, or D, even if not explicitly disclosed.
  • fouling of chromatography media can be due, at least in part, to the presence of fibrinogen/fibrin and/or other non-target proteins in blood products (e.g. plasma) used in the isolation of therapeutic proteins.
  • blood products e.g. plasma
  • the precipitant is provided in amounts that do not generate observable precipitate when applied to serum or plasma. In other embodiments of the inventive concept the precipitant is provided in amounts that generate observable precipitate when applied to serum or plasma.
  • the amount of precipitant used can vary depending upon the nature of the precipitant. Suitable precipitants are preferably nondenaturing, and can include organic acids and salts of organic acids (e.g. sodium citrate), inorganic salts (e.g. ammonium sulfate, sodium sulfate, sodium chloride), and hydrophilic polymers (e.g. PEG, dextran, etc.).
  • organic acids and salts of organic acids e.g. sodium citrate
  • inorganic salts e.g. ammonium sulfate, sodium sulfate, sodium chloride
  • hydrophilic polymers e.g. PEG, dextran, etc.
  • an organic salt such as sodium citrate it can be provided during thawing of frozen plasma at concentrations ranging from about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 15%, 18%, or less than about 20% (w/v).
  • an inorganic salt such as ammonium sulfate
  • an inorganic salt such as ammonium sulfate
  • it can be provided during thawing of frozen plasma at concentrations ranging from about 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 12%, 15%, 18%, or less than about 20% (w/v).
  • a hydrophilic polymer such as PEG is used it can be provided during thawing of frozen plasma at concentrations ranging from about 0.1%, 0.2%, 0.5%, 0.7%, 1%, 1.5%, 2%, 2.5%, 3%, 4%, 5%, 6% 8%, or less than about 10% (w/v).
  • a precipitant can be provided as a dry solid, preferably a powder or crystalline powder, that is added directly to the thawing plasma.
  • a precipitant can be provided as a concentrated stock solution, which can be added in volumes sufficiently small as to not significantly impact the volume of the thawing plasma.
  • a stock solution can contain the precipitant at a concentration that is from 5-fold to 100-fold higher than the desired final concentration.
  • the precipitant can be added gradually while mixing.
  • the concentration of the precipitant in the precipitating mixture gradually increases throughout the volume of the mixture until the final desired concentration is reached.
  • the precipitant can be added as a single bolus.
  • a region of the precipitating mixture near the point of addition can transiently have concentrations of the precipitant that are greater than the target concentration, however undesired precipitate resulting from such transient elevations will solvate as the concentration of precipitant equilibrates.
  • the modified cryoprecipitate has a different and distinct composition from that of a cryoprecipitate formed from the same source plasma without the addition of the precipitant.
  • the modified cryoprecipitate can have an increased amount of fibrin, fibrinogen, or denatured/partially denatured proteins relative to a corresponding conventional cryoprecipitate.
  • modified cryoprecipitate can be a more desirable product for isolation of cold-insoluble proteins (such as fibrinogen, clotting factors, etc.) than conventional cryoprecipitate, for example providing higher yield per unit of frozen plasma.
  • a modified cryo-poor plasma can have a different and distinct composition from that of a conventional cryo-poor plasma produced by cryoprecipitation of the same source plasma in the absence of the precipitant.
  • the modified cryo-poor plasma can have a reduced content of fibrinogen, fibrin, and/or denatured or partially denatured proteins relative to conventional cryo-poor plasma without significantly impacting the content of cold-soluble proteins.
  • This reduced protein content can permit application of such a modified cryo-poor plasma directly to a chromatography media without intervening precipitation and/or significant dilution steps.
  • minor dilution of modified cryo-poor plasma may be required depending upon the nature or the chromatography media.
  • cryo-poor plasma can be diluted from about 1:1.1, 1:1.25, 1:1.5, 1:1.75, 1:2, 1:2.5, or up to about 1:3 prior to application to the chromatography media.
  • Chromatography media can have any suitable formulation and configuration. Suitable chromatography media can be formulated to provide separation by size exclusion ion exchange, hydrophobic interaction, affinity, and/or mixed mode interactions. Suitable media can be provided as porous granules or beads, non-porous granules or beads, filters, fibers, and/or porous membranes. Structural portions of chromatography media can be based on any suitable materials. Examples include but are not limited to polysaccharides (such as cross-lined dextran), synthetic polymers, and/or inorganic materials (such as hydroxyapatite). Chromatography media can be provided in any suitable geometry.
  • Suitable geometries include open or sealed chromatography columns, radial chromatography columns, cartridges, membrane housings, etc.
  • granular or bead-based chromatography media can be added directly to a modified cryo-poor plasma as a loose material, rather than being contained in a device or enclosure through which the modified cryo-poor plasma is passed.
  • volume ratio of modified cryo-poor plasma to chromatography media can range from about 1:1 to 1:20, depending upon the protein to be recovered and the capacity of the chromatography media for the protein.
  • lack of fouling can also reduce the need for extensive and/or harsh washing conditions (e.g. high or low pH, high or low salt concentrations, surfactants, enzymes, etc.) for regeneration of chromatography media following use. This can advantageously reduce the time required for regeneration, thereby improving turnaround time in what is frequently a bottleneck step in protein purification processes.
  • the ability to use relatively mild washing/regeneration conditions can increase the number of useful cycles for a chromatography media (particularly affinity chromatography media). This advantageously reduces the need to replace or replenish the media.
  • modifications to the cryo-poor plasma may be necessary prior to application to a chromatography media in order to meet the pH or ionic strength requirements for the media’s separation mode.
  • pH may need to be adjusted by the addition of a small volume of acid or base prior to application to ion exchange media.
  • ionic strength may need to be reduced (e.g. by dialysis or the use of desalting media) prior to application to ion exchange media.
  • ionic strength may need to be increased (for example, by the addition of a salt) prior to application to hydrophobic interaction media.
  • a variety of pharmaceutically useful proteins can be obtained from methods of the inventive concept at high yield and specific activity.
  • Such proteins include fibrinogen, factor VII, factor VIII, factor IX, factor XIII, von Willebrand factor, fibronectin, immunoglobulins, alpha-1 antitrypsin, protein C, protein S, Cl-esterase inhibitor, antithrombin III, thrombin, and/or albumin.
  • a unit of frozen plasma is obtained and allowed to thaw at a temperature of from 1 °C to 6 °C.
  • sodium citrate is added (either by addition of dry sodium citrate or by a small volume of a 50% (w/v) sodium citrate stock solution) to give a final concentration of 8% or less.
  • the modified cryo-poor plasma is separated from solid materials (i.e. the modified cryoprecipitate). This can be accomplished by filtration, centrifugation, decanting, or any suitable technique.
  • the modified cryoprecipitate can be recovered and solubilized for further processing and recovery of pharmaceutical proteins that are relatively cold-insoluble (e.g. fibrinogen, factor VIII, factor XIII, von Willibrand factor, and/or fibronectin).
  • the recovered cryo-poor plasma is applied to an affinity chromatography media without intervening precipitation, preparative filtration (e.g. molecular weight or size specific filtration), and/or dilution steps to recover pharmaceutically valuable proteins that are relatively cold soluble.
  • the modified cryo-poor plasma can be applied to a protein-A or protein-G functionalized affinity chromatography media without intervening precipitation or dilution steps, then the media washed and eluted with a low pH buffer to recover immunoglobulin G.
  • a procion blue functionalized affinity chromatography media can be used to recover albumin.
  • an affinity chromatography media functionalized with an antibody specific for a desired pharmaceutically valuable protein can be used to recover the desired protein.
  • an antibody is directed to alpha- 1 antitrypsin.

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  • Chemical & Material Sciences (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Biochemistry (AREA)
  • Biophysics (AREA)
  • Genetics & Genomics (AREA)
  • Medicinal Chemistry (AREA)
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  • Gastroenterology & Hepatology (AREA)
  • Toxicology (AREA)
  • Engineering & Computer Science (AREA)
  • Dentistry (AREA)
  • Wood Science & Technology (AREA)
  • Environmental Sciences (AREA)
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  • Analytical Chemistry (AREA)
  • Immunology (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Peptides Or Proteins (AREA)

Abstract

L'invention concerne un procédé de production d'un précipité pauvre en agent cryogénique modifié qui peut être utilisé en chromatographie sans étapes de précipitation intermédiaires. Pendant la décongélation du plasma congelé à basse température, un composé précipitant (par exemple un sel d'un acide organique) est ajouté en petites quantités. Le plasma pauvre en agent cryogénique modifié obtenu présente une tendance réduite à encrasser les milieux de chromatographie, permettant une application directe à de tels milieux sans avoir besoin d'étapes de précipitation supplémentaires. Le cryoprécipité modifié obtenu présente une teneur plus élevée en protéines insolubles dans le froid (tels que des facteurs de coagulation), et peut être resolubilisé et traité ultérieurement.
PCT/US2020/012860 2019-09-20 2020-01-09 Compositions et procédés de génération d'un plasma pauvre en agent cryogénique modifié WO2021054997A1 (fr)

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US201962903613P 2019-09-20 2019-09-20
US62/903,613 2019-09-20

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Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4435318A (en) * 1981-05-22 1984-03-06 Ionics, Incorporated Electrodialysis preparation of purified AHF concentrate
US4727059A (en) * 1985-03-28 1988-02-23 Serotherapeutisches Institut Wien Gesellschaft M.B.H. Fibronectin solution suitable for use in humans and process for its preparation
US4977246A (en) * 1989-06-06 1990-12-11 Rorer Pharmaceutical Corporation High recovery process for antihemophilic factor
US5259951A (en) * 1990-06-12 1993-11-09 Sclavo S.P.A. Process for the purification of factor VIII and factor VIII obtained by said process
US20090221491A1 (en) * 2006-01-25 2009-09-03 Andrea Neisser-Svae Purification and Use of a Factor for Supporting Wound Healing

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4435318A (en) * 1981-05-22 1984-03-06 Ionics, Incorporated Electrodialysis preparation of purified AHF concentrate
US4727059A (en) * 1985-03-28 1988-02-23 Serotherapeutisches Institut Wien Gesellschaft M.B.H. Fibronectin solution suitable for use in humans and process for its preparation
US4977246A (en) * 1989-06-06 1990-12-11 Rorer Pharmaceutical Corporation High recovery process for antihemophilic factor
US5259951A (en) * 1990-06-12 1993-11-09 Sclavo S.P.A. Process for the purification of factor VIII and factor VIII obtained by said process
US20090221491A1 (en) * 2006-01-25 2009-09-03 Andrea Neisser-Svae Purification and Use of a Factor for Supporting Wound Healing

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